Antibiotic resistance is a major scientific issue threating human health. Broad spectrum even extended-spectrum drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), pan-resistant Acinetobacter baumannii, carbapenems-resistant Pseudomonas aeruginosa render treatment of some infections difficult, and act as important dangerous factors in death of patients with these infections. At present, the mutational speed of drug-resistant bacteria is faster than the development of novel antibacterial drugs, and people are helpless to treat some drug-resistant bacteria and challenged with so-called “post-antibiotic era”. Hence, it is extremely urgent to develop novel antibacterial drugs, especially new drugs having bactericidal ability to broad and extended spectrum drug-resistant bacteria.
Cationic antibacterial peptides are a group of small molecular polypeptides with broad spectrum antibacterial activity, and act as important immune defense for organisms to combat microorganism invasion. Cationic antibacterial peptides have antibacterial effects featured with fast bactericidal speed, broad bactericidal spectrum and difficult to develop resistance, and thus have been regarded as ideal candidates for novel antibiotics. The action mechanism of cationic antibacterial peptides relates to positive charges carried thereon, which can bind to bacterial surface with negative charges, embed in bacterial cell membrane, form voids and destroy membranal integrity, so that bacterial cytoplasm drains and bacteria die finally. In comparison with bactericidal targets of conventional antibiotics such as protein bodies, RNA enzymes, the cationic antibacterial peptides have direct, rapid and strong bactericidal potency, and are not prone to inducing conventional drug-resistances relying on gene mutation, hydrolases and so on. Some antibacterial peptides have been used as antibiotics against drug-resistant bacteria, and entered clinical trial (M. Zasloff, Nature, 2002, 415, 389-395).
Human defensin-5 (HD-5) is a natural cationic antibacterial peptide mainly expressed on intestinal mucosa, and has relatively strong bactericidal effects on many bacteria such as Escherichia coli, Staphylococcus aureus, Bacillus cereus, Enterobacter aerogenes and fugi. In addition, HD-5 exerts immunomodulatory effects via regulating release of intestinal local inflammatory factors. Hence, HD-5 plays a very important role in intestinal immuno-barrier.
Although the extraction and artificial synthesis of HD-5 are conventional now, when completely simulating natural HD-5, the antibacterial activity is prone to being influenced by many in vivo environmental factors, for example, the presence of sodium chloride in physiological concentration may extremely deduce the antibacterial activity, which restrict the use of HD-5 in developing novel antibacterial drugs suitable for industrial production and clinical application.
Hence, the present invention intends to modify HD-5 according to physical and chemical properties of HD-5, overcome functional drawbacks of HD-5 and make it to be promising in developing novel antibacterial drugs.